Neurotoxicity Stress Research Articles

Organophosphorus-based chemical additives induced behavioral changes in zebrafish (Danio rerio): Swimming activity is a sensitive stress indicator

Organophosphorus flame retardants (OPFRs) have been extensively used as chemical additives in polymer based consumer products. Among them, Isopropylphenyl phosphate (IPPP) and tripropyl phosphate (TPP) are predominant, which have potential to cause neuro-toxic effects on non-target organisms. As behavior (swimming activity) response is the first adjustment due to neurotoxic stress on the fitness of fish. In this study, the quantified swimming activity of zebrafish (Danio rerio) under IPPP and TPP exposure in an online monitoring system was investigated to assess the neurotoxin effects under long-term exposure periods, no swimming anomalies were observed in the control group. Whereas, in the OPFR exposures ((treatment I: 5 μg/L and treatment II: 25 μg/L), a series of anomalies were identified. Hyperactivity was shown in IPPP treatment I group (5 μg/L), whereas zebrafish swimming activity was declined throughout the study period in IPPP treatment II (25 μg/L), and TPP groups (5 μg/L and 25 μg/L) when compared to the control group. Circadian rhythm was not affected in the present study. The results of the present study indicated that the fitness of test individuals was a valid biomarker for eco-toxicity assessment under unescapable conditions. Hypoactivity of zebrafish signified the neurotoxic effects of IPPP and TPP. A concentration based improvement in swimming activity was observed under recovery conditions, which suggested that recovery capacity along with toxicity responses could be a comprehensive non-invasive technique to assess the eco-toxicity of waterborne chemicals.

Reexamination of diathesis stress and neurotoxic stress theories: A qualitative review of pre-trauma neurobiology in relation to posttraumatic stress symptoms.

ObjectiveAssociations of neurobiological differences with posttraumatic stress disorder (PTSD) have generated interest in their temporal relation. Support has been voiced for the neurotoxic stress theory (NST) in which neurobiological differences develop following exposure and PTSD development. In contrast, the diathesis stress theory (DST) posits that neurobiological differences existed prior to exposure and may be vulnerability factors for PTSD. Studies in the first wave of neurobiological PTSD research were all cross sectional, but a second wave of research followed which used prospective repeated‐measures designs that measured neurobiology prior to trauma exposure experiences, allowing greater causal inference.MethodsThis study reviewed the second‐wave studies in hopes of developing a preliminary consensus to support either the NST or the DST based on this more powerful prospective, repeated‐measures study design.ResultsTwenty‐five second‐wave studies were located that measured neurobiology prior to traumatic experiences. Nineteen studies supported the DST. Of 10 studies that were capable of testing the NST, only 3 were supportive.ConclusionThe implications of the NST versus the DST have profound implications for understanding the fragility of the human brain and possible paths forward for future research on assessment, treatment, and social policy.

<p>The Potential Neuroprotective Role of Citicoline in Hepatic Encephalopathy</p>

PurposeHepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE.Materials and MethodsMice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue.ResultsThe result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal’s locomotor activity and improved brain tissue markers of oxidative stress.ConclusionThese data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE.

Proteomic analysis of human iPSC-derived sensory neurons implicates cell stress and microtubule dynamics dysfunction in bortezomib-induced peripheral neurotoxicity

The neurotoxic effects of the chemotherapeutic agent bortezomib on dorsal root ganglia sensory neurons are well documented, yet the mechanistic underpinnings that govern these cellular processes remain incompletely understood. In this study, system-wide proteomic changes were identified in human induced pluripotent stem cell-derived sensory neurons (iSNs) exposed to a clinically relevant dose of bortezomib. Label-free mass spectrometry facilitated the identification of approximately 2800 iSN proteins that exhibited differential levels in the setting of bortezomib. A significant proportion of these proteins affect the cellular processes of microtubule dynamics, cytoskeletal and cytoplasmic organization, and molecular transport, and pathway analysis revealed an enrichment of proteins in signaling pathways attributable to the unfolded protein response and the integrated stress response. Alterations in microtubule-associated proteins suggest a multifaceted relationship exists between bortezomib-induced proteotoxicity and microtubule cytoskeletal architecture, and MAP2 was prioritized as a topmost influential candidate. We observed a significant reduction in the overall levels of MAP2c in somata without discernable changes in neurites. As MAP2 is known to affect cellular processes including axonogenesis, neurite extension and branching, and neurite morphology, its altered levels are suggestive of a prominent role in bortezomib-induced neurotoxicity.

Integrated Hypoxia Signaling and Oxidative Stress in Developmental Neurotoxicity of Benzo[a]Pyrene in Zebrafish Embryos.

Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon formed by the incomplete combustion of organic matter. Environmental B[a]P contamination poses a serious health risk to many organisms because the pollutant may negatively affect many physiological systems. As such, chronic exposure to B[a]P is known to lead to locomotor dysfunction and neurodegeneration in several organisms. In this study, we used the zebrafish model to delineate the acute toxic effects of B[a]P on the developing nervous system. We found that embryonic exposure of B[a]P downregulates shh and isl1, causing morphological hypoplasia in the telencephalon, ventral thalamus, hypothalamus, epiphysis and posterior commissure. Moreover, hypoxia-inducible factors (hif1a and hif2a) are repressed upon embryonic exposure of B[a]P, leading to reduced expression of the Hif-target genes, epo and survivin, which are associated with neural differentiation and maintenance. During normal embryogenesis, low-level oxidative stress regulates neuronal development and function. However, our experiments revealed that embryonic oxidative stress is greatly increased in B[a]P-treated embryos. The expression of catalase was decreased and sod1 expression increased in B[a]P-treated embryos. These transcriptional changes were coincident with increased embryonic levels of H2O2 and malondialdehyde, with the levels in B[a]P-treated fish similar to those in embryos treated with 120-μM H2O2. Together, our data suggest that reduced Hif signaling and increased oxidative stress are involved in B[a]P-induced acute neurotoxicity during embryogenesis.

Linagliptin, the dipeptidyl peptidase-4 enzyme inhibitor, lessens CHOP and GRP78 biomarkers levels in cisplatin-induced neurobehavioral deficits: A possible restorative gateway.

Cisplatin (CP) is a cornerstone chemotherapeutic agent, however, its neurotoxicity is a chief cause of its limited usage. Linagliptin, which is a dipeptidyl peptidase-4 enzyme inhibitor, has exhibited considerable neuroprotective potential. We aimed to evaluate the linagliptin modulatory effects on endoplasmic reticulum (ER) stress, redox status, and apoptosis in CP-induced neurotoxicity. Thirty mice were allocated equally into the control group, Group II: CP group, and Group III: linagliptin treated CP group. All groups were subjected to the measurement of hippocampal messenger RNA gene expression of glucose-regulated protein-78 and C/EBP homologous protein (CHOP). Peroxisome proliferator-activated receptor γ coactivator 1α and cleaved caspase-3 levels were assessed by the enzyme-linked immunosorbent assay technique while malondialdehyde, reduced glutathione levels and superoxide dismutase activity were detected spectrophotometrically. Linagliptin ameliorated ER stress and enhanced antioxidant status with cognitive function improvement. Linagliptin may be considered a promising neuroprotective agent owing to its ability to reduce ER/oxidative stress.

Experimental Exposure of Lumbricus terrestris to Microplastics

The effects of microplastic exposure in aquatic organisms have been widely reported. Nonetheless, there is limited evidence of the effects of exposure in soil systems. Thus, the objective of this study was to evaluate the effects of microplastic exposure using as a bioindicator the species Lumbricus terrestris, exposed to different concentrations of microplastic (2.5%; 5%, and 7% w/w). Avoidance bioassays were carried out for 48 h in soil with and without microplastic; the gastrointestinal tract—crop/gizzard, foregut, and midgut—was dissected and acetylcholinesterase (AChE) was used as a biomarker of neurotoxicity stress. In parallel, bioassays of microplastic ingestion were carried out, and after 48 h of initiating the ingestion assay, using a stereo and fluorescence microscope, the microplastic distribution was observed in the different earthworm segments. The results obtained in the avoidance assay indicated a lack of preference for either soil type; however, upon moving, the earthworms lost surface mucus, resulting in burns and lesions on their bodies, which were reflected in the increase in AChE enzyme levels, which was not directly related to microplastic ingestion, but rather likely acts as an external physical stress agent. The results of the ingestion bioassay showed that microplastic was present in all the earthworm segments, with a higher number of particles in the hindgut. The Lumbricus terrestris did not distinguish microplastics from soil particles, and given the high exposure concentrations, microplastics produced physical lesions on the mucus membranes of earthworms. Lumbricus terrestris showed to be a suitable bioindicator for testing the exposure to microplastic contamination in soil.

Oxidative stress and mitochondrial dysfunction in organophosphate pesticide-induced neurotoxicity and its amelioration: a review

Organophosphorus pesticides (OPs) are widely used for controlling pests worldwide. The inhibitory effects of these pesticides on acetylcholinesterase lead to neurotoxic damages. The oxidative stress is responsible for several neurological diseases, including Parkinson's disease, seizure, depression, and Alzheimer's disease. Strong evidence suggests that dysfunction of mitochondria and oxidative stress are involved in neurological diseases. OPs can disturb the function of mitochondria by inducing oxidative stress. In the present study, we tried to highlight the role of dysfunction of mitochondria and the induction of oxidative stress in the neurotoxicity induced by OPs. Additionally, the amelioration of OP-induced oxidative damage and mitochondrial dysfunctional through the chemical and natural antioxidants have been discussed.

The mechanism of CaMK2α-MCU-mitochondrial oxidative stress in bupivacaine-induced neurotoxicity

Ca2+/calmodulin dependent protein kinase2α (CaMK2α) is a serine/threonine protein kinase in neurons and leads to neuronal injury when it is activated abnormally. Bupivacaine, a local anesthetic commonly used in regional nerve block, could induce neurotoxicity via apoptotic injury. Whether or not CaMK2α is involved in bupivacaine-induced neurotoxicity and it is regulated remains unclear. In this study, bupivacaine was administered for intrathecal injection in C57BL/6 mice for building vivo injury model and was used to culture human neuroblastoma (SH-SY5Y) cells for building vitro injury model. The results showed that bupivacaine induced mitochondrial oxidative stress and neurons apoptotic injury, promoted phosphorylation of CaMK2α and cAMP-response element binding protein (CREB), and elevated mitochondrial Ca2+ uniporter (MCU) expression. Furthermore, it induced CaMK2α phosphorylation at Thr286 which phosphorylated CREB at Ser133 and up-regulated MCU transcriptional expression. Inhibition of CaMK2α-MCU signaling with knock-down of CaMK2α and MCU or with inhibitors (KN93 and Ru360) significantly mitigated bupivacaine-induced neurotoxic injury. Over-expression of CaMK2α significantly enhanced above oxidative injury. Activated MCU with agonist (spermine) reversed protective effect of siCaMK2α on bupivacaine-induced mitochondrial oxidative stress. Our data revealed that CaMK2α-MCU-mitochondrial oxidative stress pathway is a major mechanism whereby bupivacaine induces neurotoxicity and inhibition of above signaling could be a therapeutic strategy in the treatment of bupivacaine-induced neurotoxicity.

Tetrabromobisphenol A-Induced Apoptosis in Neural Stem Cells Through Oxidative Stress and Mitochondrial Dysfunction.

Tetrabromobisphenol A (TBBPA) is widely used in materials like plastics and textiles as a fire retardant. In a previous study, we reported TBBPA might disrupt hippocampal neurogenesis and neurocognitive function in mice. However, the mechanism responsible for these effects has not been established. The present study was undertaken to investigate the potential involvement of oxidative stress and mitochondrial dysfunction in TBBPA-mediated neurotoxicity in neural stem cells. We confirmed TBBPA was more cytotoxic to neural stem cells than to neurons, astrocytes, or fibroblasts, and found that TBBPA-induced neural stem cell apoptosis was accompanied by increased reactive oxygen species generation and mitochondrial dysfunction. At a molecular level, TBBPA-induced apoptosis was determined to be mediated by c-Jun N-terminal kinase-p53 pathway activation. Taken together, these findings suggest that the adverse effects of TBBPA on hippocampal neurogenesis are due to the inhibition of neural stem cell expansion.

Environmentally relevant concentration of chromium induces nuclear deformities in erythrocytes and alters the expression of stress-responsive and apoptotic genes in brain of adult zebrafish

Heavy metal contamination of water body has become a serious threat to aquatic life forms specially to fish. Hexavalent chromium (Cr [VI]) is one of the most potent heavy metal toxicant. It is present in aquatic environment at concentrations beyond permissible limit. Considering the fact that toxic effects are function of the exposure concentration, studies involving toxicological risk assessment should be done at environmentally relevant concentration. Therefore we studied the toxic effects of Cr [VI] to zebrafish at an environmentally relevant concentration (2 mg L−1). We monitored the genotoxic potential of Cr [VI] in erythrocytes through a simple reliable microscopic assay and found an increase in frequency of micronucleated erythrocytes along with erythrocytes with blebbed, lobed and notched nuclei. In addition, Cr [VI] induced neurotoxicity, being a least reported event was also investigated. Histological alterations in brain, elevated GSH and MDA content and increased catalase activity indicated oxidative stress-mediated damage. This was further confirmed through expressional alteration of Ucp2. Upregulation of Nrf2, Nqo1 and Ho1 clearly indicated the involvement of Nrf2-ARE system in stress response against Cr [VI] induced neurotoxicity. The transcriptional induction of apoptotic genes such as Bax, Caspase 9 and Caspase 3 along with downregulation of Bcl2 indicated that the cytoprotective system failed to counter the induced stress. Interestingly, there was upregulation of AChE gene, which could be correlated with the upregulated apoptotic genes. This study provides an insight on the neurotoxic stress of Cr [VI] on the zebrafish yet at an environmentally relevant concentration. Moreover the induction of nuclear anomalies in the erythrocytes can serve as extremely sensitive endpoints of toxicological stress indicators of aquatic contaminants like Cr [VI].

Promoting the Assessment of Physical Activity and Cardiorespiratory Fitness in Assessing the Role of Vascular Risk on Cognitive Decline in Older Adults.

The world population has been experiencing significant aging processes that have resulted in rising proportions of older persons in the total population since the mid-twentieth century. It is estimated that by 2025 there will be 1.2 billion people over 60 years of age and by 2050 there will be 2 billion, with 80% in developing countries (World Health Organization, 2011) Moreover, the recent (Alzheimer's Disease International., 2018) indicates that over 50 million people live with dementia worldwide, which is expected to exceed 152 million by 2050. There is no known cure for dementia and, thus, preventative strategies are of great importance. In fact, the annual cost of dementia care was expected to exceed $1 trillion by 2018, thereby, primary prevention is currently considered a potential tool to delay the disease onset by modulating modifiable risk factors. In fact, it has been suggested around 35% of dementia is attributable to a combination of nine modifiable risk factors, including education, hypertension, obesity, hearing loss, depression, diabetes, physical inactivity, smoking, and social isolation (Livingston et al., 2017). In line with that, three potential brain mechanisms through which preventative strategies may reduce dementia risk are: (a) reduced brain damage (vascular, neurotoxic and oxidative stress), (b) reduced brain inflammation, and (c) increased brain cognitive reserve with greater physical activity (PA) and exercise suggested as a common factor to promote all these mechanisms (Livingston et al., 2017). Therefore, greater PA and fitness (especially cardiorespiratory fitness, CRF) are currently considered key factors to promote in the prevention of cognitive decline and dementia (Kennedy et al., 2017; Livingston et al., 2017; Muller et al., 2017). Moreover, these key factors not only directly affecting cognitive decline and dementia, but also have effect through their mediation effects on other related risk factors, such as hypertension, obesity, depression, and diabetes (Chase et al., 2009; Kokkinos et al., 2017; Celis-Morales et al., 2018; Chekroud et al., 2018; Ortega et al., 2018). Particularly well-established in the literature is the role of PA and CRF on cardiovascular (CV) risk factors and diseases (CVD), as well as mortality (Blair et al., 1998; Jimenez-Pavon et al., 2016; Ortega et al., 2018). However, studies analyzing the role of vascular risk on cognitive decline have been based solely upon the use of the Framingham Heart Study general cardiovascular disease score (i.e., Framingham Risk Score (FRS) (Eldholm et al., 2018; Rabin et al., 2018), and no studies have investigated the potential mediation effect of PA and CRF on the vascular risk of cognitive decline and dementia. Hence, we believe that to better understand the relationship between vascular risk and cognitive decline, assessment of PA and CRF should be included when determining an individual's vascular risk factors. Therefore, the purpose of this opinion article is to encourage the assessment of PA and fitness, at least CRF, when studying the role of vascular risk on cognitive decline.

Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein.

The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn2+-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn2+ exposure. Welders exposed to Mn2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn2+-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.

Methcathinone Induces Oxidative Stress to Mediate Neurotoxicity Through Activating Apoptosis and Autophagy

Background: Methcathinone (CAT) acts as a designer psychostimulant and the beta-keto analog of methamphetamine, is globally abused and cause serious neurological conditions. The aim of this study is to analyze neurotoxicity of Methcathinone (CAT) to verify the hypothesis of unbalanced oxidative stress and the evaluation of apoptotic response and autophagy by sub-acute exposure to high dosage injection. Methods: To address these issues, we measured the body temperature and stereotyped motor activity during rats model setting by CAT injection in 15-day. Biochemical markers of oxidative stress were evaluated, and the activity of anti-oxidative enzymes was found significantly lower in the brains of rats that had different doses of CAT. Findings: The mechanism of the toxicological effect of CAT is proved to be partly induced by apoptotic pathway according to multiple biochemical and immunohistological methods, as well as expression of nNOS, ratios of LC3-II to LC3-I and cleaved caspase3 to procaspase3. Furthermore, we detected the inhibition of NAC to CAT induced-apoptotic and autophagy pathways effected largely compared to the CAT group through activity of SOD, GSH, GSH-PX, CAT and MDA, TUNEL staining and expression of Atg-7, Beclin-1 and ratio of LC3-II to LC3-I, which decreased neurotoxicity. Our results highlight the central role of oxidative stress in CAT neurotoxicity, as high levels of apoptosis and autophagy can promote the progression of neurotoxicity. Funding Statement: This study was supported by National Natural Science Foundation of China (Grant No. 81501632). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal procedures were conducted between 8:00 A.M. and 8:00 P.M. in strict accordance with the “Hubei Administration Rule of Laboratory Animal” and were approved by the Institutional Animal Care and Use Committee of Huazhong University of Science and Technology, Tongji Medical College, China (approval No. Y20100377). The description of animal procedures meets the ARRIVE recommended national standard “Laboratory Animal-Requirements of Environment and Housing Facilities”.

Neuroprotective Effects of N - Acetyl - Methoxytryptamine in a Neurotoxic Mice Model of Huntington’s Disease Induced by Quinolinic Acid

Huntington’s Disease (HD) is an autosomal dominant neuropathology associated with severe degeneration in neurons of the basal ganglia. It is characterized by progressive motors symptoms, cognitive deficits and dementia. The genetic mutation induces trinucl eotide repeat expansion (TNR) of cytosine, adenine and guanine (CAG). The CAG - repeat is translated into a poly glutamine (polyQ) stretch caused by molding of DNA “loop out” structures and DNA slippage during the replication. This expanded sequence encodes a mutant huntingtin (mHtt), which is associated to neuronal dysfunction, cellular death, ubiquitous molecular and cellular anomalies. Furthermore, there are progressive impairments in motor control, cognitive function and mood. Quinolinic acid (QA) is an e xcitotoxic compound in humans and animals that has been linked to HD. N - acetyl - methoxytryptamine (MLT) is a hormone that produce anti - oxidant and anti - inflammatory effects on cell damage. The principal aim of this study is to know if QA induces damage in s triatal astrocytes and neurons and to evidence how MLT can participate as a neuroprotectant agent against the neurotoxic injury. We inoculate QA intrastriatal in 8 weeks old wild type (WT) female mice as endogenous neurotoxic model of HD. Here, we worked w ith three different groups of mice, and the striatal injection was administrated in all animals. PBS were inoculated in control mice; the second group was injected only QA; and the last group was pre - treated with MLT 30 min before the QA injection. Immunob lots, oxidative stress biomarkers, histological assay of astrocytes and neurons were evaluated as well as rotarod and open field tests. There was a reduction in proteins levels of BDNF and NeuN in QA mice. Contrary effects in lysates showed NF - κB, IκB α , HT T, GFAP and NRs. The analysis of CAT, SOD, Gpx and GSH showed decreased activity, while MDA displayed increased activation in QA mice. The animals pre - treated with MLT revers the tendency of proteins and antioxidant biomarkers; the HTT perinuclear staining in neurons was reduced. NeuN histochemistry showed a greater number of NeuN + cells; the astrogliosis was attenuated; and locomotor activities improved. Analysis of RT - PCR do no show significant diferences between teatments. This study suggests that MLT c an induce a compensatory response to neurotoxic stress againts neuro - glial injury. Thus, increasing MLT levels may be a promising treatment for HD disorder.

50-Hz MF does not affect global DNA methylation of SH-SY5Y cells treated with the neurotoxin MPP.

Exposure to extremely low frequency magnetic fields (ELF-MFs) has been associated with an increased risk of neurodegenerative disorders. The underlying mechanisms, however, are still debated. Since epigenetics play a key role in the neurodegenerative process, we investigated whether exposure to ELF-MF (50 Hz, 1 mT) might affect global DNA methylation of SH-SY5Y dopaminergic-like neuroblastoma cells. We assessed the percentage of 5-methylcytosine (5-mC) of three repetitive interspersed sequences (ALU, LINE-1, or SATα), through pyrosequencing analysis. We demonstrated that ELF exposure (up to 72 h) does not induce any change in the methylation pattern of ALU, LINE-1, and SATα in both proliferating and differentiated SH-SY5Y cells. Furthermore, when administered in combination with 1-methyl-4-phenylpyridinium (MPP+ ), a neurotoxin mimicking the Parkinson's Disease (PD) phenotype, ELF-MF exposure does not trigger any modulation in the percentage of 5-mC of the repetitive elements. Our findings demonstrate that exposure to 50-Hz MF does not affect global DNA methylation in proliferating and dopaminergic differentiated SH-SY5Y cells, either under basal culture conditions or under neurotoxic stress. Bioelectromagnetics. 40:33-41, 2019. © 2018 Bioelectromagnetics Society.

Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

Astrocyte reactivity is disease- and stimulus-dependent, adopting either a proinflammatory A1 phenotype or a protective, anti-inflammatory A2 phenotype. Recently, we demonstrated, using cell culture, animal models and human brain samples, that dopaminergic neurons produce and secrete higher levels of the chemokine-like signaling protein Prokineticin-2 (PK2) as a compensatory protective response against neurotoxic stress. As astrocytes express a high level of PK2 receptors, herein, we systematically characterize the role of PK2 in astrocyte structural and functional properties. PK2 treatment greatly induced astrocyte migration, which was accompanied by a shift in mitochondrial energy metabolism, a reduction in proinflammatory factors, and an increase in the antioxidant genes Arginase-1 and Nrf2. Overexpression of PK2 in primary astrocytes or in the in vivo mouse brain induced the A2 astrocytic phenotype with upregulation of key protective genes and A2 reactivity markers including Arginase-1 and Nrf2, PTX3, SPHK1, and TM4SF1. A small-molecule PK2 agonist, IS20, not only mimicked the protective effect of PK2 in primary cultures, but also increased glutamate uptake by upregulating GLAST. Notably, IS20 blocked not only MPTP-induced reductions in the A2 phenotypic markers SPHK1 and SCL10a6 but also elevation of the of A1 marker GBP2. Collectively, our results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes, which could be exploited for development of novel therapeutic strategies for PD and other related chronic neurodegenerative diseases. PK2 signals through its receptors on astrocytes and promotes directed chemotaxis. PK2-induced astrocyte reactivity leads to an increase in antioxidant and anti-inflammatory proteins while increasing glutamate uptake, along with decreased inflammatory factors. © 2018 Wiley Periodicals, Inc.

Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone

Introduction: Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice.Materials and methods: Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria.Results: Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia.Conclusion: UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.

Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review.

Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cδ has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA.

Electronegative Low-Density Lipoprotein L5 Impairs Viability and NGF-Induced Neuronal Differentiation of PC12 Cells via LOX-1

There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer’s disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear. Here, PC12 cell culture was used for treatments with human LDLs (L1, L5, or oxLDL), and subsequently cell viability and nerve growth factor (NGF)-induced neuronal differentiation were assessed. We identified L5 as a neurotoxic LDL, as demonstrated by decreased cell viability in a time- and concentration-dependent manner. Contrarily, L1 had no such effect. L5 caused cell damage by inducing ATM/H2AX-associated DNA breakage as well as by activating apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1) signaling to p53 and ensuring cleavage of caspase-3. Additionally, sublethal L5 long-termly inhibited neurite outgrowth in NGF-treated PC12 cells, as evidenced by downregulation of early growth response factor-1 and neurofilament-M. This inhibitory effect was mediated via an interaction between L5 and LOX-1 to suppress NGF-induced activation of PI3k/Akt cascade, but not NGF receptor TrkA and downstream MAPK pathways. Together, our data suggest that L5 creates a neurotoxic stress via LOX-1 in PC12 cells, thereby leading to impairment of viability and NGF-induced differentiation. Atherogenic L5 likely contributes to neurodegenerative disorders.